# NM_020549.5(CHAT):c.2067C>T (p.Ile689=)

https://sugi.bio/variant/chat-p-ile689

## Summary

**CHAT p.Ile689= (c.2067C>T)** is classified **Benign** in CHAT (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 32.2%, eas) — too common for a highly-penetrant pathogenic allele; Associated with congenital myasthenic syndrome 6.

**At a glance:** Benign · review: Multiple submitters · rsID rs3793801 · 7 submitters · 1 linked condition · common (popmax 32.2%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CHAT gene that is classified as benign — not considered disease-causing, submitted by 7 submitters, and is linked to congenital myasthenic syndrome 6.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009689/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHAT](https://sugi.bio/atlas/gene/CHAT/) |
| Protein change (HGVS p.) | p.Ile689= |
| Coding change (HGVS c.) | c.2067C>T |
| MANE Select transcript | [NM_020549](https://www.ncbi.nlm.nih.gov/nuccore/NM_020549) |
| dbSNP | [rs3793801](https://www.ncbi.nlm.nih.gov/snp/rs3793801/) |
| Variant type | single nucleotide variant |
| Location | chr10:49664866-49664866 (GRCh38) |
| ClinVar | [VCV128722](https://www.ncbi.nlm.nih.gov/clinvar/variation/128722/) |

**All HGVS expressions:** `NC_000010.10:g.50872912C>T`, `NC_000010.11:g.49664866C>T`, `NG_011797.1:g.60772C>T`, `NM_001142929.2:c.1713C>T`, `NM_001142933.2:c.1821C>T`, `NM_001142934.2:c.1713C>T`, `NM_020549.5:c.2067C>T`, `NM_020984.4:c.1713C>T`, `NM_020985.4:c.1713C>T`, `NM_020986.4:c.1713C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 32.2%, eas) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.411, GERP -0.999, phastCons 0.515 — weakly conserved position
- CADD: **PHRED 15.09**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **32.2%** (eas) · FAF95 31.8% · FAF99 31.6% · 14,461/44,874 in the highest group · 23,549/1,614,196 alleles overall — common (popmax 32.2%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 32.2% | 3 |
| South Asian | 5.31% | 19 |
| Remaining individuals (not grpmax-eligible) | 2.12% | 47 |
| Finnish (not grpmax-eligible) | 1.29% | 78 |
| Middle Eastern | 1.06% | 95 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.909% | 110 |
| Admixed American | 0.212% | 473 |
| African / African-American | 0.172% | 582 |
| European (non-Finnish) | 0.128% | 783 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CHAT** population constraint: LOEUF 0.973, pLI 9.9145e-17, missense-Z 0.67235; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **congenital myasthenic syndrome 6** — Definitive (AR)

## Protein context {#protein}

Residue **689** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 84.73, 75% of residues very-high.

**8 experimental structure(s)** (PDB): [2FY2](https://www.rcsb.org/structure/2FY2), [2FY3](https://www.rcsb.org/structure/2FY3), [2FY4](https://www.rcsb.org/structure/2FY4), [2FY5](https://www.rcsb.org/structure/2FY5), [7AMD](https://www.rcsb.org/structure/7AMD), [9F84](https://www.rcsb.org/structure/9F84).

## What this gene does {#gene-function}

*Describes the biological roles of CHAT (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

CHAT participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of PC](https://reactome.org/content/detail/R-HSA-1483191) | curated |
| [Acetylcholine Neurotransmitter Release Cycle](https://reactome.org/content/detail/R-HSA-264642) | other |

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (6 Benign, 1 Likely benign).

**Submission history:** 7 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2017-03-31 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2015-03-09 |
| Genetic Services Laboratory, University of Chicago | Likely benign | no assertion criteria provided | clinical testing |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2018-08-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[congenital myasthenic syndrome 6](https://sugi.bio/atlas/disease/congenital-myasthenic-syndrome-6/).

**Reported phenotype names (ClinVar):** Familial infantile myasthenia, not specified, not provided, AllHighlyPenetrant, none provided, MYASTHENIC SYNDROME, CONGENITAL, 6, PRESYNAPTIC, Congenital myasthenic syndrome type 6, MYASTHENIC SYNDROME, PRESYNAPTIC, CONGENITAL, ASSOCIATED WITH EPISODIC APNEA.

## Pharmacogenomics (PharmGKB) {#pgx}

Drugs with reported response associations: donepezil;galantamine;rivastigmine.
*PharmGKB levels 1A/1B (highest) → 4. Discuss any medication decision with your prescriber — reference information, not advice.*

## Similar variants {#similar}

Related CHAT variant pages (same residue, condition, or type): [CHAT c.1282-2A>T](/variant/chat-c-1282-minus-2a-t), [CHAT c.1840-9A>G](/variant/chat-c-1840-minus-9a-g), [CHAT c.698+1G>T](/variant/chat-c-698-plus-1g-t), [CHAT c.698+2T>C](/variant/chat-c-698-plus-2t-c), [CHAT p.Ala557Thr](/variant/chat-p-ala557thr), [CHAT p.Arg151Ter](/variant/chat-p-arg151ter), [CHAT p.Arg207Gly](/variant/chat-p-arg207gly), [CHAT p.Arg207His](/variant/chat-p-arg207his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 128722). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*